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Summary

Epidemiology

The prevalence is unknown; more than 100 cases of NAFD have been published.

Clinical description

NAFD is characterized by mandibulofacial anomalies that include downward slant of palpebral fissures, ptosis of upper lids, coloboma of lower lids, deficiency of eyelashes of the medial one-third to two-thirds of the lower eyelids, hypoplasia of the malar eminences, hypoplasia of the maxilla, cleft palate, absence or hypopoplasia of the palatal velum, choanal atresia, extension of a ''tongue'' of temporal hair down the sides of the cheeks. Cleft lip is rare. Limb defects are predominantly preaxial with hypoplasia or absence of thumbs being the most characteristic feature, frequently associated with radio-ulnar synostosis and/or aplasia/hypoplasia of the radius. Triphalangeal thumbs and other abnormalities of the digits have also been reported and a small percentage of patients also have lower limb malformations. Otologic and oral anomalies frequently lead to bilateral conductive hearing loss, speech difficulties and upper respiratory airways obstruction. Most Nager syndrome individuals have normal vision and intelligence.

Etiology

In approximately 50% of patients, NAFD has been associated with heterozygous mutations in the SF3B4 gene (1q21.2), coding for a component of the splicing machinery.

Diagnostic methods

Diagnosis is based on physical and radiological examination or the identification of a mutation in SF3B4.

Differential diagnosis

Differential diagnosis may include mandibulofacial dysostosis syndromes such as Treacher-Collins syndrome, and other acrofacial dysostoses (AFD) such as the AFD Catania type, the AFD Palagonia type, the AFD Genee-Wiedemann type, the AFD Rodriquez type as well as mandibulofacial dysostosis with microcephaly (see these terms). Patients with the oculoauriculovertebral (OAV) spectrum (see this term) may also have overlapping features.

Antenatal diagnosis

Antenatal diagnosis can be performed by ultrasonography or molecular testing of SF3B4.

Genetic counseling

Nager syndrome is likely genetically heterogenous with confirmed autosomal dominant inheritance, but autosomal recessive inheritance is suspected based on sibling recurrence in consanguineous families. Genetic counseling requires careful evaluation of parents and sibs of an affected child, in order to determine if the disease has a familial origin or if it occurred sporadically. If one parent is mildly affected, recurrence risk is 50% and a 25% risk cannot be excluded when parents are apparently normal.

Management and treatment

Management must focus on neonatal respiratory distress (tracheostomy) and feeding difficulties (gastrostomy). Surgery can be considered for repair of clefts, management of severe micrognathia as well as temporomandibular joint dysfunction. Hearing aids can be proposed. Language and phonological impairment must be managed by a specific speech therapy.

Prognosis

After infancy, most patients are healthy and are presumed to have a normal lifespan. Ongoing medical issues are usually only related to airway obstruction or temporomandibular joint dysfunction in patients with more severe manbibular malformations.

Research activities on this disease

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